Lovastatin or Mevinolin represented by formula (I) is a valuable hypocholesteremic drug, which inhibits biosynthesis of cholesterol by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). Its inhibition leads to reduction in the rate of formation of cholesterol in the human body.

Lovastatin of formula (I) known chemically as (1S, 3R, 7S, 8S, 8a R)1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-napthalenyl-(S) -2-methylbutyrate is disclosed in U.S. Pat. No. 4,231,938.
Generally, Lovastatin of formula (I) is obtained through fermentation, comprising cultivating a microorganism belonging to the genus Aspergillus in an aqueous medium containing carbohydrates, yeast, inorganic salts like sodium chloride, ammonium phosphate etc assimilable by the microorganism.

The fermentation is generally carried out at ambient temperature, preferably, between 20-37° C. and pH range of 6.0 to 8.0, to give mevinolinic acid of formula (II). Lovastatin (I) is obtained and isolated from the fermentation broth after lactonisation of the acid (II) in the presence of an acid.
Several methods are known for isolation of Lovastatin (I) through lactonisation of Mevinolinic acid (II), which are summarized herein below:    1. U.S. Pat. No. 4,231,938 (Monaghan R. L et al) describes a method for isolation of Lovastatin (I) from a fermentation broth which comprises obtaining Mevinolinic acid (II) by fermentation from an aqueous medium containing a microorganism known as Aspergillus terreus and sources of carbon, nitrogen and inorganic salts assimilable by the microorganism. The fermentation is carried out between pH 6.0 to 8.0 and temperature range of 20-37° C. The broth containing Mevinolinic acid (II) is filtered and acidified to pH 4.0 with concentrated hydrochloric acid and extracted with ethyl acetate. Evaporation of the organic layer gives impure Lovastatin (I) as syrupy oil, which is then purified by column chromatography on silica gel.
However, this method has little industrial application since it involves purification by chromatography.    2. BG60460A (T. G. Dimitar et al) teaches a method for isolation of Lovastatin (I), which comprises alkaline treatment of the cultured broth at pH 8.5-9.0 followed by filtration, acidification and extraction with an organic solvent. The organic extract after concentration is purified by ultrafiltration/reverse osmosis and finally recrystallised from ethyl acetate, butyl acetate or ethanol.
The purification method involving reverse filtration or reverse osmosis, is however not attractive for industrial manufacture.    3. PCT Application No WO 97/20834 A1. (Dimov I et al) describes a method for isolation of Lovastatin (I) from the culture broth which comprises treatment of the broth with an alkaline base in the presence of an anti-oxidant and inert filler, between pH 9.5-13.0 after which the fermentation broth is filtered and the mycelia cake is washed with a dilute solution of an alkaline base. The mixture thus obtained is acidified with a mineral acid between pH 2.5-4.0 to give Mevinolinic acid (II), which is filtered and dissolved in a chlorinated hydrocarbon. The acid (II) is lactonised by heating the mixture to give Lovastatin (I), which is then concentrated. The impure product (I) is recrystallized several times from a mixture of acetonitrile, tert-butylmethyl ether, and butyl chloride.
The method, however, suffers from the following shortcomings in that, it is lengthy involving additional unit operations of alkaline pretreatment of the culture broth with a base followed by acidification and filtration to give Mevinolinic acid (II). Moreover, it utilizes acetonitrile, which has a low flash point i.e. 2° C., which renders its use on a commercial scale a hazardous proposition.    4. U.S. Pat. No. 5,202,029 (Haytko P. N et al) claims a method for purification of Lovastatin (I) using high performance liquid chromatography (HPLC). This method of purification is not suited for industrial use due to its high cost.    5. U.S. Pat. No. 5,712,130 (Hajko P et al) discloses a method for isolation of Lovastatin (I) by extracting the acidified fermentation broth containing Mevinolinic acid (II) with butyl acetate. The organic layer is concentrated under reduced pressure above 40° C., during which lactone formation takes place with simultaneous removal of water giving Lovastatin (I) with purity of 90%.    6. U.S. Pat. No. 6,387,258 B1 (K. Vilmos et al) describes a method of isolation and purification of statin compounds which comprises alkaline pretreatment of the fermentation broth in the presence of a hydrophobic solvent like isobutyl acetate and a de-emulsifier like dodecyl trimethyl ammonium chloride. The purified fermentation broth after acidification to pH between 2.0-4.5 with sulfuric acid is extracted with isobutyl acetate and the organic extract concentrated to give impure Lovastatin (I) which is purified by recrystallisation from ethanol/water mixture. The procedure is, however, lengthy involving multiple steps of initial alkaline pretreatment, acidification, lactonisation and isolation of impure Lovastatin (I), and therefore, less attractive for industrial manufacture. It is pertinent to mention that the isolated yield of Lovastatin. (I) is quite low, without alkaline pretreatment of the fermentation broth.    7. U.S. Patent Application 2002/0156298 A1 (McManus, J et al) teaches a method for lactonisation of Mevinolinic acid (II) wherein the lactonisation is carried out with a strong mineral acid at a temperature lower than 10° C. in presence of solvents like acetonitirile, dimethyl sulfoxide, tetrahydrofuran and dioxane.    8. U.S. patent application Ser. No. 5,917,058 (Y. Kumar, et al) describes a method for isolation of Lovastatin (I) using acetic acid as solvent in absence of strong acid with mild heating till 55° C.
However, isolation of Lovastatin (I) by this method is tedious since it involves removal of excess acetic acid by neutralization with a base, which results in salts of acetic acid, which have to be removed thoroughly prior to crystallisation of Lovastatin (I). Another drawback is the impurity formation resulting from the esterification reaction between 3-hydroxy group of the 3-hydroxy lactone and acetic acid.    9. U.S. patent application Ser. No. 5,939,564 (Y. Kumar, et al) teaches a method for lactonisation of Mevinolinic acid (II) to give Lovastatin (I) using a mild catalyst such as a pyridine salt of a mineral or organic acid for carrying out the transformation. The lactonisation is carried out in a polar alcoholic or non-alcoholic solvent at 42-45° C. and the resulting Lovastatin (I) is isolated by addition of water.    10. US Patent Application 2002/0147351 A1 (T. H. A Peters, et al) teaches a method for isolation of Lovastatin (I) by lactonisation of Mevinolinic acid (II) or its ammonium salt, using a lactonising agent such as methanesulfonic acid, phosphorous pentoxide, acidic ion-exchange resin, molecular sieves, acidic clay, silica gel and combinations thereof in a water miscible solvent like acetonitrile or immiscible solvent like dichloromethane at room temperature to bind water to form a insoluble complex which shifts the equilibrium towards lactone formation.    11. PCT Application No. WO 02/00615 A2 (P. Kumar; et. al) describes a method for lactonisation and isolation of Lovastatin (I) from the fermentation broth. The method comprises acidification of the broth with a mineral acid followed by lactonisation in an aqueous medium at 50-60° C. The broth is filtered and the mycelia cake extracted with an organic solvent, which is then concentrated to a reduced volume and subsequently filtered to give Lovastatin (I) having purity around 95%.
The method described in WO 02/00615 suffers from the following shortcomings in that,    i) lactonisation of the hydroxy acid requires a long time between 20-60 hrs which is lengthy by any industrial manufacturing standard,    ii) the method involves multiple unit operations, comprising initial lactonisation in an aqueous medium, followed by extraction with an organic solvent,
Moreover, it was found that replication of the method described in WO 02/00615 gave Lovastatin (I) with only 54% yield, which needless to mention, is not an attractive commercial proposition.    12. U.S. Patent Application 2003/0050482 A1 (Lee K. H et al) relates to a method for isolation of Lovastatin (I) by lactonisation of the acid (II) or its ammonium salt in the presence of dehydrating agents like magnesium sulfate, sodium sulfate, calcium chloride, molecular sieves etc instead of an acidic medium in an inert atmosphere. Lactonisation of mevinolinic acid (II) is carried out at a very high temperature of 100-110° C. At this temperature, Lovastatin (I) is prone to degradation, giving rise to dimeric impurity, which is difficult to remove by conventional methods.
To summarise, the prior art methods for preparing Lovastatin (I) suffer from the following disadvantages:                i) They involve sequential steps of initial alkaline pre-treatment, lactonisation of acid (II) after acidification, extraction of the lactonised product i.e., Lovastatin of formula (I) with a organic solvent followed by isolation of Lovastatin of formula (I), rendering the prior art methods lengthy and tedious,        ii) Formation of higher level of impurities, which are difficult to remove by conventional purification methods, and        iii) Utilization of expensive and highly sophisticated purification methods such as chromatography, reverse osmosis, ultrafiltration etc, and/or use of solvents like acetonitrile having low flash points.        
Regulatory authorities all over the world are becoming very stringent about the level of impurities in an approved drug. Especially, there is a growing concern about the nature of impurities present in such molecules. Pharmacopoeial specification requires that the impurities such as the dimeric impurity in Lovastatin (I), which is difficult to remove by conventional methods, should be below 0.2%.
Needless, to mention most of the prior art methods do not give product conforming to the above mentioned criteria.
Therefore, there exists a need for a method for manufacture of lovastatin of the formula (I), which is not only simple, efficient, cost effective, but also gives Lovastatin (I) in high yield and purity, substantially free of impurities.